2-pyridylamino-4-nitrile-piperidinyl orexin receptor antagonists

ABSTRACT

The present invention is directed to 2-pyridylamino-4-nitrile-piperidinyl compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the 2-pyridylamino-4-nitrile-piperidinyl compounds described herein in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to pharmaceutical compositions comprising these compounds. The present invention is also directed to uses of these pharmaceutical compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

BACKGROUND OF THE INVENTION

The orexins (hypocretins) comprise two neuropeptides produced in thehypothalamus: the orexin A (OX-A) (a 33 amino acid peptide) and theorexin B (OX-B) (a 28 amino acid peptide) (Sakurai T. et al., Cell,1998, 92, 573-585). Orexins are found to stimulate food consumption inrats suggesting a physiological role for these peptides as mediators inthe central feedback mechanism that regulates feeding behavior (SakuraiT. et al., Cell, 1998, 92, 573-585). Orexins regulate states of sleepand wakefulness opening potentially novel therapeutic approaches fornarcoleptic or insomniac patients (Chemelli R. M. et al., Cell, 1999,98, 437-451). Orexins have also been indicated as playing a role inarousal, reward, learning and memory (Harris, et al., Trends Neurosci.,2006, 29 (10), 571-577). Two orexin receptors have been cloned andcharacterized in mammals. They belong to the super family of G-proteincoupled receptors (Sakurai T. et al., Cell, 1998, 92, 573-585): theorexin-1 receptor (OX or OX1R) is selective for OX-A and the orexin-2receptor (OX2 or OX2R) is capable to bind OX-A as well as OX-B. Thephysiological actions in which orexins are presumed to participate arethought to be expressed via one or both of OX1 receptor and OX2 receptoras the two subtypes of orexin receptors.

SUMMARY OF THE INVENTION

The present invention is directed to2-pyridylamino-4-nitrile-piperidinyl compounds which are antagonists oforexin receptors. The present invention is also directed to uses of the2-pyridylamino-4-nitrile-piperidinyl compounds described herein in thetreatment or prevention of neurological and psychiatric disorders anddiseases in which orexin receptors are involved. The present inventionis also directed to pharmaceutical compositions comprising thesecompounds. The present invention is also directed to uses of thesepharmaceutical compositions in the prevention or treatment of suchdiseases in which orexin receptors are involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:A is selected from the group consisting of phenyl, naphthyl andheteroaryl;R^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

(1) hydrogen,

-   -   (2) halogen,    -   (3) hydroxyl,    -   (4) —(C═O)_(m)—O_(n)—C₁₋₆ alkyl, where m is 0 or 1, n is 0 or 1        (wherein if m is 0 or n is 0, a bond is present) and where the        alkyl is unsubstituted or substituted with one or more        substituents selected from R⁴,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R⁴,    -   (6) —(C═O)_(m)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R⁴,    -   (7) —(C═O)_(m)—C₂₋₄ alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R⁴,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-naphthyl, where        the phenyl or naphthyl is unsubstituted or substituted with one        or more substituents selected from R⁴,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one or more substituents        selected from R⁴,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently        selected from the group consisting of:        -   (a) hydrogen,        -   (b) C₁₋₆ alkyl, which is unsubstituted or substituted with            R⁴,        -   (c) C₃₋₆ alkenyl, which is unsubstituted or substituted with            R⁴,        -   (d) C₃₋₆ alkynyl, which is unsubstituted or substituted with            R⁴,        -   (e) C₃₋₆cycloalkyl which is unsubstituted or substituted            with R⁴,        -   (f) phenyl, which is unsubstituted or substituted with R⁴,            and        -   (g) heterocycle, which is unsubstituted or substituted with            R⁴,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)R¹², where q is 0, 1 or 2 and where R¹² is        selected from the definitions of R¹⁰ and R¹¹,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;        R³ is selected from C₁₋₆alkyl and C₃₋₆cycloalkyl, which is        unsubstituted or substituted with one or more substituents        selected from R⁴;        R⁴ is selected from the group consisting of:    -   (1) hydroxyl,    -   (2) halogen,    -   (3) C₁₋₆ alkyl,    -   (4) —C₃₋₆ cycloalkyl,    -   (5) —O—C₁₋₆ alkyl,    -   (6) —O(C═O)—C₁₋₆ alkyl,    -   (7) —NH₂,    -   (7) —NH—C₁₋₆alkyl,    -   (8) —NO₂,    -   (9) phenyl,    -   (10) heterocycle,    -   (11) —CO₂H, and    -   (12) —CN;        R⁵ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (5) C₃₋₆ cycloalkyl, which is unsubstituted or substituted with        C₁₋₆ alkyl, halogen, hydroxyl or phenyl,    -   (6) —O—C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl, and    -   (7) —S—C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl;        R⁶ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) C₁₋₆ alkyl, which is unsubstituted or substituted with oxo,        halogen, hydroxyl or phenyl,    -   (3) C₂₋₆ alkenyl, and    -   (4) —(CO)—O—C₁₋₆ alkyl;        or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa:

wherein R^(1a), R^(1b), R^(1c), R³ and R⁵ are defined herein; or apharmaceutically acceptable salt thereof

An embodiment of the present invention includes compounds of the formulaIa′:

wherein R^(1a), R^(1b), R^(1c), R³ and R⁵ are defined herein; or apharmaceutically acceptable salt thereof

An embodiment of the present invention includes compounds of the formulaIa″:

wherein R^(1a), R^(1b), R^(1c), R³ and R⁵ are defined herein; or apharmaceutically acceptable salt thereof

An embodiment of the present invention includes compounds of the formulaIb:

wherein R^(1a), R^(1b), R³ and R⁵ are defined herein; or apharmaceutically acceptable salt thereof

An embodiment of the present invention includes compounds of the formulaIb′:

wherein R^(1a), R^(1b), R³ and R⁵ are defined herein; or apharmaceutically acceptable salt thereof

An embodiment of the present invention includes compounds of the formulaIb″:

wherein R^(1a), R^(1b), R³ and R⁵ are defined herein; or apharmaceutically acceptable salt thereof

An embodiment of the present invention includes compounds of the formulaIc:

wherein R^(1a), R³ and R⁵ are defined herein; or a pharmaceuticallyacceptable salt thereof

An embodiment of the present invention includes compounds of the formulaIc′:

wherein R^(1a), R³ and R⁵ are defined herein; or a pharmaceuticallyacceptable salt thereof

An embodiment of the present invention includes compounds of the formulaIc″:

wherein R^(1a), R³ and R⁵ are defined herein; or a pharmaceuticallyacceptable salt thereof

An embodiment of the present invention includes compounds wherein A isselected from phenyl, pyridyl, thiophenyl, thiazolyl, isothiazolyl, andpyrazolyl. An embodiment of the present invention includes compoundswherein A is phenyl. An embodiment of the present invention includescompounds wherein A is pyridyl. An embodiment of the present inventionincludes compounds wherein A is thiophenyl. An embodiment of the presentinvention includes compounds wherein A is thiazolyl. An embodiment ofthe present invention includes compounds wherein A is isothiazolyl. Anembodiment of the present invention includes compounds wherein A ispyrazolyl.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (5) —O—C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) heteroaryl, wherein heteroaryl is selected from triazolyl,        tetrazolyl, oxazolyl, pyrrolyl, imidazolyl, indolyl, pyridyl,        and pyrimidinyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,    -   (7) phenyl, which is unsubstituted or substituted with halogen,        hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl or —NO₂,    -   (8) —O-phenyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆ alkyl or —NO₂,    -   (9) —CN, and    -   (10) —NH—C₁₋₆ alkyl, or —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        and —O—C₁₋₆alkyl.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (5) —O—C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) —CN, and    -   (7) heteroaryl, wherein heteroaryl is selected from triazolyl,        tetrazolyl, oxazolyl, pyrrolyl, imidazolyl, indolyl, pyridyl,        and pyrimidinyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen,    -   (4) —O—C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen,    -   (5) —CN, and    -   (6) heteroaryl, wherein heteroaryl is selected from triazolyl,        tetrazolyl, oxazolyl, pyrrolyl, imidazolyl, indolyl, pyridyl,        and pyrimidinyl.

An embodiment of the present invention includes compounds wherein R^(1c)is hydrogen, and R^(1a) and R^(1b) are independently selected from thegroup consisting of:

-   -   (1) hydrogen,    -   (2) fluoro,    -   (3) chloro,    -   (4) bromo,    -   (5) methyl,    -   (6) ethyl,    -   (7) trifluoromethyl, and    -   (8) heteroaryl, wherein heteroaryl is selected from triazolyl,        tetrazolyl, oxazolyl, pyrrolyl, imidazolyl, indolyl, pyridyl,        and pyrimidinyl.

An embodiment of the present invention includes compounds wherein R^(1c)is hydrogen, R^(1b) is hydrogen, and R^(1a) is independently selectedfrom the group consisting of:

-   -   (1) triazolyl,    -   (2) tetrazolyl,    -   (3) oxazolyl,    -   (4) pyrrolyl,    -   (5) imidazolyl,    -   (6) pyridyl, and    -   (7) pyrimidinyl.

An embodiment of the present invention includes compounds wherein R^(1c)is hydrogen, R^(1b) is hydrogen, and R^(1a) is independently selectedfrom the group consisting of:

-   -   (1) triazolyl,    -   (2) tetrazolyl, and    -   (3) pyrimidinyl.

An embodiment of the present invention includes compounds wherein R³ isC₁₋₆ alkyl. An embodiment of the present invention includes compoundswherein R³ is C₃₋₆ cycloalkyl. An embodiment of the present inventionincludes compounds wherein R³ is methyl or ethyl. An embodiment of thepresent invention includes compounds wherein R³ is methyl. An embodimentof the present invention includes compounds wherein R³ is (R)-methyl.

An embodiment of the present invention includes compounds wherein R⁵ isis selected from the group consisting of:

-   -   (1) hydrogen,    -   (2) chloro,    -   (3) C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen,    -   (4) C₃₋₆ cycloalkyl, which is unsubstituted or substituted with        C₁₋₆ alkyl or halogen,    -   (5) —O—C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen, and    -   (6) —S—C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen.

An embodiment of the present invention includes compounds wherein R⁵ isselected from the group consisting of: hydrogen, methyl, cyclopropyl,chloro, —O—CH₃ and —S—CH₃.

An embodiment of the present invention includes compounds wherein R⁵ ishydrogen. An embodiment of the present invention includes compoundswherein R⁵ is methyl. An embodiment of the present invention includescompounds wherein R⁵ is cyclopropyl. An embodiment of the presentinvention includes compounds wherein R⁵ is chloro. An embodiment of thepresent invention includes compounds wherein R⁵ is —O—CH₃. An embodimentof the present invention includes compounds wherein R⁵ is —S—CH₃.

An embodiment of the present invention includes compounds wherein R⁶ isis selected from the group consisting of:

-   -   (1) hydrogen,    -   (2) C₁₋₆ alkyl,    -   (3) C₂₋₆ alkenyl, and    -   (4) —(CO)—O—C₁₋₆ alkyl.

An embodiment of the present invention includes compounds wherein R⁶ isselected from the group consisting of: hydrogen, methyl, ethyl, propyl,propenyl, and —(CO)—O—CH₃.

An embodiment of the present invention includes compounds wherein R⁶ ishydrogen. An embodiment of the present invention includes compoundswherein R⁶ is methyl. An embodiment of the present invention includescompounds wherein R⁶ is ethyl. An embodiment of the present inventionincludes compounds wherein R⁶ is propyl. An embodiment of the presentinvention includes compounds wherein R⁶ is propenyl. An embodiment ofthe present invention includes compounds wherein R⁶ is —(CO)—O—CH₃.

Certain embodiments of the present invention include a compound which isselected from the group consisting of the subject compounds of theExamples herein or a pharmaceutically acceptable salt thereof

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds. Formula I showsthe structure of the class of compounds without specificstereochemistry.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Thecoupling reaction is often the formation of salts using anenantiomerically pure acid or base. The diasteromeric derivatives maythen be converted to the pure enantiomers by cleavage of the addedchiral residue. The racemic mixture of the compounds can also beseparated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As appreciated by those of skill in the art, halogen or halo as usedherein are intended to include fluoro, chloro, bromo and iodo.Similarly, C₁₋₆, as in C₁₋₆ alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement,such that C₁₋₈alkyl specifically includes methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. A groupwhich is designated as being independently substituted with substituentsmay be independently substituted with multiple numbers of suchsubstituents. The term “heterocycle” as used herein includes bothunsaturated and saturated heterocyclic moieties, wherein the unsaturatedheterocyclic moieties (i.e. “heteroaryl”) include benzoimidazolyl,benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzothiazolyl, benzotriazolyl, benzothiophenyl, benzoxazepin,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, dihydroindolyl, indolazinyl, indazolyl,isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline,oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl,quinoxalinyl, tetrahydroquinoxalinyl, tetrazolyl, tetrazolopyridyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, and N-oxides thereof, andwherein the saturated heterocyclic moieties include azetidinyl,1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,thiomorpholinyl, and tetrahydrothienyl, and N-oxides thereof.

The present invention also includes all pharmaceutically acceptableisotopic variations of a compound of the Formula I in which one or moreatoms is replaced by atoms having the same atomic number, but an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes suitable for inclusion inthe compounds of the invention include isotopes of hydrogen such as ²Hand 3H, carbon such as ¹¹C, ¹³C and ¹⁴C, nitrogen such as ¹³N and ¹⁵N,oxygen such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus such as ³²P, sulfur such as³⁵S, fluorine such as ¹⁸F, iodine such as ¹²³I and ¹²⁵I, and chlorinesuch as ³⁶Cl. Certain isotopically-labelled compounds of Formula I, forexample those incorporating a radioactive isotope, are useful in drugand/or substrate tissue distribution studies. The radioactive isotopestritium, i.e. 3H, and carbon-14, i.e. ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection. Substitution with heavier isotopes such as deuterium, i.e.2H, may afford certain therapeutic advantages resulting from greatermetabolic stability, for example, increased in vivo half-life or reduceddosage requirements, and hence may be preferred in some circumstances.Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labelled compoundsof Formula I can generally be prepared by conventional techniques knownto those skilled in the art or by processes analogous to those describedin the accompanying Examples using appropriate isotopically-labelledreagents in place of the non-labelled reagent previously employed.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particular embodiments includethe ammonium, calcium, magnesium, potassium, and sodium salts. Salts inthe solid form may exist in more than one crystal structure, and mayalso be in the form of hydrates. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particular embodiments include the citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual enantiomers or diastereomersthereof.

The subject compounds are useful in a method of antagonizing orexinreceptor activity in a patient such as a mammal in need of suchinhibition comprising the administration of an effective amount of thecompound. The present invention is directed to the use of the compoundsdisclosed herein as antagonists of orexin receptor activity. In additionto primates, especially humans, a variety of other mammals may betreated according to the method of the present invention. The presentinvention is directed to a compound of the present invention or apharmaceutically acceptable salt thereof that could be useful inmedicine. The present invention may further be directed to a use of acompound of the present invention or a pharmaceutically acceptable saltthereof for the manufacture of a medicament for antagonizing orexinreceptor activity or treating the disorders and diseases noted herein inhumans and animals.

The subject treated in the present methods is generally a mammal, suchas a human being, male or female. The term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. It is recognized that one skilled in the art may affect theneurological and psychiatric disorders by treating a patient presentlyafflicted with the disorders or by prophylactically treating a patientafflicted with the disorders with an effective amount of the compound ofthe present invention. As used herein, the terms “treatment” and“treating” refer to all processes wherein there may be a slowing,interrupting, arresting, controlling, or stopping of the progression ofthe neurological and psychiatric disorders described herein, but doesnot necessarily indicate a total elimination of all disorder symptoms,as well as the prophylactic therapy of the mentioned conditions,particularly in a patient who is predisposed to such disease ordisorder. The terms “administration of and or” administering a” compoundshould be understood to mean providing a compound of the invention or aprodrug of a compound of the invention to the individual in needthereof.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof

The utility of the compounds in accordance with the present invention asorexin receptor OX1R and/or OX2R antagonists may be readily determinedwithout undue experimentation by methodology well known in the art,including the “FLIPR Ca²⁺ Flux Assay” (Okumura et al., Biochem. Biophys.Res. Comm. 280:976-981, 2001). In a typical experiment the OX1 and OX2receptor antagonistic activity of the compounds of the present inventionwas determined in accordance with the following experimental method. Forintracellular calcium measurements, Chinese hamster ovary (CHO) cellsexpressing the rat orexin-1 receptor or the human orexin-2 receptor, aregrown in Iscove's modified DMEM containing 2 mM L-glutamine, 0.5 g/mlG418, 1% hypoxanthine-thymidine supplement, 100 U/ml penicillin, 100μg/ml streptomycin and 10% heat-inactivated fetal calf serum (FCS). Thecells are seeded at 20,000 cells/well into Becton-Dickinson black384-well clear bottom sterile plates coated with poly-D-lysine. Allreagents were from GIBCO-Invitrogen Corp. The seeded plates areincubated overnight at 37° CO2. and 5% CO2. Ala-6,12 human orexin-A asthe agonist is prepared as a 1 mM stock solution in 1% bovine serumalbumin (BSA) and diluted in assay buffer (HBSS containing 20 mM HEPES,0.1% BSA and 2.5 mM probenecid, pH7.4) for use in the assay at a finalconcentration of 70 pM. Test compounds are prepared as 10 mM stocksolution in DMSO, then diluted in 384-well plates, first in DMSO, thenassay buffer. On the day of the assay, cells are washed 3 times with 100μl assay buffer and then incubated for 60 min (37° C., 5% CO2) in 60 μlassay buffer containing 1 μM Fluo-4AM ester, 0.02% pluronic acid, and 1%BSA. The dye loading solution is then aspirated and cells are washed 3times with 100 μl assay buffer. 30 μl of that same buffer is left ineach well. Within the Fluorescent Imaging Plate Reader (FLIPR, MolecularDevices), test compounds are added to the plate in a volume of 25 μl,incubated for 5 min and finally 25 μl of agonist is added. Fluorescenceis measured for each well at 1 second intervals for 5 minutes and theheight of each fluorescence peak is compared to the height of thefluorescence peak induced by 70 pM Ala-6,12 orexin-A with buffer inplace of antagonist. For each antagonist, IC50 value (the concentrationof compound needed to inhibit 50% of the agonist response) isdetermined. Alternatively, compound potency can be assessed by aradioligand binding assay (described in Bergman et. al. Bioorg. Med.Chem. Lett. 2008, 18, 1425-1430) in which the inhibition constant (Ki)is determined in membranes prepared from CHO cells expressing either theOX1 or OX2 receptor. The intrinsic orexin receptor antagonist activityof a compound which may be used in the present invention may bedetermined by these assays.

All of the final compounds of the following examples had activity inantagonizing the human orexin-2 receptor in the aforementioned assayswith an IC₅₀ of about 0.1 nM to 100 nM. All of the final compounds ofthe following examples had activity in the radioligand binding assaywith a Ki of about 0.1 nM to 100 nM against the orexin-2 receptor. Allof the final compounds of the following examples had activity in theFLIPR assay with an IC50 of about 0.1 nM to 100 nM against the orexin-2receptor. Additional data is provided in the following Examples. Such aresult is indicative of the intrinsic activity of the compounds in useas antagonists of orexin-1 receptor and/or the orexin-2 receptor. Ingeneral, one of ordinary skill in the art would appreciate that asubstance is considered to effectively antagonize the orexin receptor ifit has an IC50 of less than about 50 μM, preferably less than about 100nM. With respect to other piperidine compounds such as those disclosedin WO 2010/048012, it would be desirable that the present compoundsexhibit unexpected properties, such as increased selectivity at theorexin-2 receptor relative to the orexin-1 receptor. For example,relative to certain compounds of WO2010/048012 that do not possess a2-pyridyloxy-3-substituted-4-nitrile ring, the compounds of the examplespossess greater selectivity for the orexin-2 receptor than for theorexin-1 receptor.

The orexin receptors have been implicated in a wide range of biologicalfunctions. This has suggested a potential role for these receptors in avariety of disease processes in humans or other species. The compoundsof the present invention could therefore potentially have utility intreating, preventing, ameliorating, controlling or reducing the risk ofa variety of neurological and psychiatric disorders associated withorexin receptors, including one or more of the following conditions ordiseases: sleep disorders, sleep disturbances, including enhancing sleepquality, improving sleep quality, increasing sleep efficiency,augmenting sleep maintenance; increasing the value which is calculatedfrom the time that a subject sleeps divided by the time that a subjectis attempting to sleep; improving sleep initiation; decreasing sleeplatency or onset (the time it takes to fall asleep); decreasingdifficulties in falling asleep; increasing sleep continuity; decreasingthe number of awakenings during sleep; decreasing intermittent wakingsduring sleep; decreasing nocturnal arousals; decreasing the time spentawake following the initial onset of sleep; increasing the total amountof sleep; reducing the fragmentation of sleep; altering the timing,frequency or duration of REM sleep bouts; altering the timing, frequencyor duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasingthe amount and percentage of stage 2 sleep; promoting slow wave sleep;enhancing EEG-delta activity during sleep; decreasing nocturnalarousals, especially early morning awakenings; increasing daytimealertness; reducing daytime drowsiness; treating or reducing excessivedaytime sleepiness; increasing satisfaction with the intensity of sleep;increasing sleep maintenance; idiopathic insomnia; sleep problems;insomnia, hypersomnia, idiopathic hypersomnia, repeatabilityhypersomnia, intrinsic hypersomnia, narcolepsy, interrupted sleep, sleepapnea, wakefulness, nocturnal myoclonus, REM sleep interruptions,jet-lag, shift workers' sleep disturbances, dyssomnias, night terror,insomnias associated with depression, emotional/mood disorders,Alzheimer's disease or cognitive impairment, as well as sleep walkingand enuresis, and sleep disorders which accompany aging; Alzheimer'ssundowning; conditions associated with circadian rhythmicity as well asmental and physical disorders associated with travel across time zonesand with rotating shift-work schedules, conditions due to drugs whichcause reductions in REM sleep as a side effect; fibromyalgia; syndromeswhich are manifested by non-restorative sleep and muscle pain or sleepapnea which is associated with respiratory disturbances during sleep;conditions which result from a diminished quality of sleep; increasinglearning; augmenting memory; increasing retention of memory; eatingdisorders associated with excessive food intake and complicationsassociated therewith, compulsive eating disorders, obesity (due to anycause, whether genetic or environmental), obesity-related disordersovereating, anorexia, bulimia, cachexia, dysregulated appetite control,hypertension, diabetes, elevated plasma insulin concentrations andinsulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast,prostate and colon cancer, osteoarthritis, obstructive sleep apnea,cholelithiasis, gallstones, heart disease, lung disease, abnormal heartrhythms and arrythmias, myocardial infarction, congestive heart failure,coronary heart disease, acute and congestive heart failure; hypotension;hypertension; urinary retention; osteoporosis; angina pectoris;myocardinal infarction; ischemic or haemorrhagic stroke; subarachnoidhaemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronicrenal failure; renal disease; impaired glucose tolerance; sudden death,polycystic ovary disease, craniopharyngioma, the Prader-Willi Syndrome,Frohlich's syndrome, GH-deficient subjects, normal variant shortstature, Turner's syndrome, and other pathological conditions showingreduced metabolic activity or a decrease in resting energy expenditureas a percentage of total fat-free mass, e.g, children with acutelymphoblastic leukemia, metabolic syndrome, also known as syndrome X,insulin resistance syndrome, reproductive hormone abnormalities, sexualand reproductive dysfunction, such as impaired fertility, infertility,hypogonadism in males and hirsutism in females, fetal defects associatedwith maternal obesity, gastrointestinal motility disorders, intestinalmotility dyskinesias, obesity-related gastro-esophageal reflux,hypothalmic diseases, hypophysis diseases, respiratory disorders, suchas obesity-hypoventilation syndrome (Pickwickian syndrome),breathlessness, cardiovascular disorders, inflammation, such as systemicinflammation of the vasculature, arteriosclerosis, hypercholesterolemia,hyperuricaemia, lower back pain, gallbladder disease, gout, kidneycancer, increased anesthetic risk, reducing the risk of secondaryoutcomes of obesity, such as reducing the risk of left ventricularhypertrophy; diseases or disorders where abnormal oscillatory activityoccurs in the brain, including depression, migraine, neuropathic pain,Parkinson's disease, psychosis and schizophrenia, as well as diseases ordisorders where there is abnormal coupling of activity, particularlythrough the thalamus; enhancing cognitive function, including cognitivedysfunctions that comprise deficits in all types of attention, learningand memory functions occurring transiently or chronically in the normal,healthy, young, adult or aging population, and also occurringtransiently or chronically in psychiatric, neurologic, cardiovascularand immune disorders; enhancing memory; increasing memory retention;increasing immune response; increasing immune function; hot flashes;night sweats; extending life span; schizophrenia; muscle-relateddisorders that are controlled by the excitation/relaxation rhythmsimposed by the neural system such as cardiac rhythm and other disordersof the cardiovascular system; conditions related to proliferation ofcells such as vasodilation or vasorestriction and blood pressure;cancer; cardiac arrhythmia; hypertension; congestive heart failure;conditions of the genital/urinary system; disorders of sexual functionand fertility; adequacy of renal function; responsivity to anesthetics;mood disorders, such as depression or more particularly depressivedisorders, for example, single episodic or recurrent major depressivedisorders and dysthymic disorders, or bipolar disorders, for example,bipolar I disorder, bipolar II disorder and cyclothymic disorder, mooddisorders due to a general medical condition, and substance-induced mooddisorders; affective neurosis; depressive neurosis; anxiety neurosis;anxiety disorders including acute stress disorder, agoraphobia,generalized anxiety disorder, obsessive-compulsive disorder, panicattack, panic disorder, post-traumatic stress disorder, separationanxiety disorder, social phobia, specific phobia, substance-inducedanxiety disorder and anxiety due to a general medical condition; acuteneurological and psychiatric disorders such as cerebral deficitssubsequent to cardiac bypass surgery and grafting, stroke, ischemicstroke, cerebral ischemia, spinal cord trauma, head trauma, perinatalhypoxia, cardiac arrest, hypoglycemic neuronal damage; Huntington'sChorea; Huntington's disease and Tourette syndrome; Cushing'ssyndrome/disease; basophile adenoma; prolactinoma; hyperprolactinemia;hypophysis tumor/adenoma; hypothalamic diseases; inflammatory boweldisease; gastric diskinesia; gastric ulcers; Froehlich's syndrome;adrenohypophysis disease; hypophysis disease; adrenohypophysishypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism;Kallman's syndrome (anosmia, hyposmia); functional or psychogenicamenorrhea; hypopituitarism; hypothalamic hypothyroidism;hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia;hypothalamic disorders of growth hormone deficiency; idiopathic growthdeficiency; dwarfism; gigantism; acromegaly; amyotrophic lateralsclerosis; multiple sclerosis; ocular damage; retinopathy; cognitivedisorders; idiopathic and drug-induced Parkinson's disease; muscularspasms and disorders associated with muscular spasticity includingtremors, epilepsy, convulsions, seizure disorders, absence seisures,complex partial and generalized seizures; Lennox-Gastaut syndrome;cognitive disorders including dementia (associated with Alzheimer'sdisease, ischemia, trauma, vascular problems or stroke, HIV disease,Parkinson's disease, Huntington's disease, Pick's disease,Creutzfeldt-Jacob disease, perinatal hypoxia, other general medicalconditions or substance abuse); delirium, amnestic disorders or agerelated cognitive decline; schizophrenia or psychosis includingschizophrenia (paranoid, disorganized, catatonic or undifferentiated),schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-inducedpsychotic disorder; dissociateive disorders including multiplepersonality syndromes and psychogenic amnesias; substance-relateddisorders, substance use, substance abuse, substance seeking, substancereinstatement, all types of psychological and physical addictions andaddictive behaviors, reward-related behaviors (includingsubstance-induced delirium, persisting dementia, persisting amnesticdisorder, psychotic disorder or anxiety disorder; tolerance, addictivefeeding, addictive feeding behaviors, binge/purge feeding behaviors,dependence, withdrawal or relapse from substances including alcohol,amphetamines, cannabis, cocaine, hallucinogens, inhalants, morphine,nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics);appetite, taste, eating or drinking disorders; movement disorders,including akinesias and akinetic-rigid syndromes (including Parkinson'sdisease, drug-induced parkinsonism, postencephalitic parkinsonism,progressive supranuclear palsy, multiple system atrophy, corticobasaldegeneration, parkinsonism-ALS dementia complex and basal gangliacalcification), chronic fatigue syndrome, fatigue, including Parkinson'sfatigue, multiple sclerosis fatigue, fatigue caused by a sleep disorderor a circadian rhythm disorder, medication-induced parkinsonism (such asneuroleptic-induced parkinsonism, neuroleptic malignant syndrome,neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia,neuroleptic-induced tardive dyskinesia and medication-induced posturaltremor), Gilles de la Tourette's syndrome, epilepsy, and dyskinesias[including tremor (such as rest tremor, essential tremor, posturaltremor and intention tremor), chorea (such as Sydenham's chorea,Huntington's disease, benign hereditary chorea, neuroacanthocytosis,symptomatic chorea, drug-induced chorea and hemiballism), myoclonus(including generalised myoclonus and focal myoclonus), tics (includingsimple tics, complex tics and symptomatic tics), restless leg syndromeand dystonia (including generalised dystonia such as iodiopathicdystonia, drug-induced dystonia, symptomatic dystonia and paroxymaldystonia, and focal dystonia such as blepharospasm, oromandibulardystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia,dystonic writer's cramp and hemiplegic dystonia); neurodegenerativedisorders including nosological entities such asdisinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration; epilepsy; seizure disorders;attention deficit/hyperactivity disorder (ADHD); conduct disorder;migraine (including migraine headache); headache; hyperalgesia; pain;enhanced or exaggerated sensitivity to pain such as hyperalgesia,causalgia, and allodynia; acute pain; burn pain; atypical facial pain;neuropathic pain; back pain; complex regional pain syndrome I and II;arthritic pain; sports injury pain; pain related to infection e.g. HIV,post-chemotherapy pain; post-stroke pain; post-operative pain;neuralgia; emesis, nausea, vomiting; gastric dyskinesia; gastric ulcers;Kallman's syndrome (anosmia); asthma; cancer; conditions associated withvisceral pain such as irritable bowel syndrome, and angina; eatingdisorders; urinary incontinence; substance tolerance, substancewithdrawal (including, substances such as opiates, nicotine, tobaccoproducts, alcohol, benzodiazepines, cocaine, sedatives, hypnotics,etc.); psychosis; schizophrenia; anxiety (including generalized anxietydisorder, panic disorder, and obsessive compulsive disorder); mooddisorders (including depression, mania, bipolar disorders); trigeminalneuralgia; hearing loss; tinnitus; neuronal damage including oculardamage; retinopathy; macular degeneration of the eye; emesis; brainedema; pain, including acute and chronic pain states, severe pain,intractable pain, inflammatory pain, neuropathic pain, post-traumaticpain, bone and joint pain (osteoarthritis), repetitive motion pain,dental pain, cancer pain, myofascial pain (muscular injury,fibromyalgia), perioperative pain (general surgery, gynecological),chronic pain, neuropathic pain, post-traumatic pain, trigeminalneuralgia, migraine and migraine headache and other diseases related togeneral orexin system dysfunction.

Thus, in certain embodiments the present invention may provide methodsfor: enhancing the quality of sleep; augmenting sleep maintenance;increasing REM sleep; increasing stage 2 sleep; decreasing fragmentationof sleep patterns; treating insomnia and all types of sleep disorders;treating or controlling sleep disturbances associated with diseases suchas neurological disorders including neuropathic pain and restless legsyndrome; treating or controlling addiction disorders; treating orcontrolling psychoactive substance use and abuse; enhancing cognition;increasing memory retention; treating or controlling obesity; treatingor controlling diabetes and appetite, taste, eating, or drinkingdisorders; treating or controlling hypothalamic diseases; treating orcontrolling depression; treating, controlling, ameliorating or reducingthe risk of epilepsy, including absence epilepsy; treating orcontrolling pain, including neuropathic pain; treating or controllingParkinson's disease; treating or controlling psychosis; treating orcontrolling dysthymic, mood, psychotic and anxiety disorders; treatingor controlling depression, including major depression and majordepression disorder; treating or controlling bipolar disorder; ortreating, controlling, ameliorating or reducing the risk ofschizophrenia, in a mammalian patient in need thereof which comprisesadministering to the patient a therapeutically effective amount of acompound of the present invention.

The subject compounds could further be of potential use in a method forthe prevention, treatment, control, amelioration, or reduction of riskof the diseases, disorders and conditions noted herein. The dosage ofactive ingredient in the compositions of this invention may be varied,however, it is necessary that the amount of the active ingredient besuch that a suitable dosage form is obtained. The active ingredient maybe administered to patients (animals and human) in need of suchtreatment in dosages that will provide optimal pharmaceutical efficacy.The selected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment. The dosewill vary from patient to patient depending upon the nature and severityof disease, the patient's weight, special diets then being followed by apatient, concurrent medication, and other factors which those skilled inthe art will recognize. Generally, dosage levels of between 0.0001 to 10mg/kg. of body weight daily are administered to the patient, e.g.,humans and elderly humans, to obtain effective antagonism of orexinreceptors. The dosage range will generally be about 0.5 mg to 1.0 g. perpatient per day which may be administered in single or multiple doses.In one embodiment, the dosage range will be about 0.5 mg to 500 mg perpatient per day; in another embodiment about 0.5 mg to 200 mg perpatient per day; and in yet another embodiment about 5 mg to 50 mg perpatient per day. Pharmaceutical compositions of the present inventionmay be provided in a solid dosage formulation such as comprising about0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mgactive ingredient. The pharmaceutical composition may be provided in asolid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 30mg, 50 mg, 80 mg, 100 mg, 200 mg or 250 mg active ingredient. For oraladministration, the compositions may be provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, such as 1,5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750,800, 900, and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, suchas once or twice per day. The compounds may be administered beforebedtime. For example, the compounds may be administered about 1 Hourprior to bedtime, about 30 minutes prior to bedtime or immediatelybefore bedtime.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of the present invention or the other drugs may have utility,where the combination of the drugs together are safer or more effectivethan either drug alone. Such other drug(s) may be administered, by aroute and in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition in unit dosage form containingsuch other drugs and the compound of the present invention iscontemplated. However, the combination therapy may also includetherapies in which the compound of the present invention and one or moreother drugs are administered on different overlapping schedules. It isalso contemplated that when used in combination with one or more otheractive ingredients, the compounds of the present invention and the otheractive ingredients may be used in lower doses than when each is usedsingly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of the present invention. Theabove combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is contemplated. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

The weight ratio of the compound of the compound of the presentinvention to the second active ingredient may be varied and will dependupon the effective dose of each ingredient. Generally, an effective doseof each will be used. Thus, for example, when a compound of the presentinvention is combined with another agent, the weight ratio of thecompound of the present invention to the other agent will generallyrange from about 1000:1 to about 1:1000, such as about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used. In such combinations the compound of the presentinvention and other active agents may be administered separately or inconjunction. In addition, the administration of one element may be priorto, concurrent to, or subsequent to the administration of otheragent(s).

The compounds of the present invention may be administered incombination with other compounds which are known in the art to be usefulfor enhancing sleep quality and preventing and treating sleep disordersand sleep disturbances, including e.g., sedatives, hypnotics,anxiolytics, antipsychotics, antianxiety agents, antihistamines,benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2antagonists including 5HT-2A antagonists and 5HT-2A/2C antagonists,histamine antagonists including histamine H3 antagonists, histamine H3inverse agonists, imidazopyridines, minor tranquilizers, melatoninagonists and antagonists, melatonergic agents, other orexin antagonists,orexin agonists, prokineticin agonists and antagonists,pyrazolopyrimidines, T-type calcium channel antagonists,triazolopyridines, and the like, such as: adinazolam, allobarbital,alonimid, alprazolam, amitriptyline, amobarbital, amoxapine,armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion,busprione, butabarbital, butalbital, capromorelin, capuride,carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide,clomipramine, clonazepam, cloperidone, clorazepate, clorethate,clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014,eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam,flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam,gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine,indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline,MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate,methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone,NGD-2-73, nisobamate, nitrazepam, nortriptyline, ornortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, ramelteon, reclazepam, roletamide,secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine,tiagabine, tracazolate, tranylcypromaine, trazodone, triazolam,trepipam, tricetamide, triclofos, trifluoperazine, trimetozine,trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone,zolpidem, and salts thereof, and combinations thereof, and the like, orthe compound of the present invention may be administered in conjunctionwith the use of physical methods such as with light therapy orelectrical stimulation.

In another embodiment, the subject compound may be employed incombination with other compounds which are known in the art, eitheradministered separately or in the same pharmaceutical compositions,including, but are not limited to: insulin sensitizers including (i)PPARy antagonists such as glitazones (e.g. ciglitazone; darglitazone;englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone;troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641,and LY-300512, and the like); (iii) biguanides such as metformin andphenformin; (b) insulin or insulin mimetics, such as biota, LP-100,novarapid, insulin detemir, insulin lispro, insulin glargine, insulinzinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7)(insulintropin); and GLP-1 (7-36)-NH2); (c) sulfonylureas, such asacetohexamide; chlorpropamide; diabinese; glibenclamide; glipizide;glyburide; glimepiride; gliclazide; glipentide; gliquidone; glisolamide;tolazamide; and tolbutamide; (d) α-glucosidase inhibitors, such asacarbose, adiposine; camiglibose; emiglitate; miglitol; voglibose;pradimicin-Q; salbostatin; CKD-711; MDL-25,637; MDL-73,945; and MOR 14,and the like; (e) cholesterol lowering agents such as (i) HMG-CoAreductase inhibitors (atorvastatin, itavastatin, fluvastatin,lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, andother statins), (ii) bile acid absorbers/sequestrants, such ascholestyramine, colestipol, dialkylaminoalkyl derivatives of across-linked dextran; Colestid®; LoCholest®, and the like, (ii)nicotinyl alcohol, nicotinic acid or a salt thereof, (iii)proliferator-activater receptor a agonists such as fenofibric acidderivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate),(iv) inhibitors of cholesterol absorption such as stanol esters,beta-sitosterol, sterol glycosides such as tiqueside; and azetidinonessuch as ezetimibe, and the like, and (acyl CoA:cholesterolacyltransferase (ACAT)) inhibitors such as avasimibe, and melinamide,(v) anti-oxidants, such as probucol, (vi) vitamin E, and (vii)thyromimetics; (f) PPARα agonists such as beclofibrate, benzafibrate,ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil; andother fabric acid derivatives, such as Atromid®, Lopid® and Tricor®, andthe like, and PPARα agonists as described in WO 97/36579; (g) PPARδagonists, such as those disclosed in WO97/28149; (h) PPAR α/δ agonists,such as muraglitazar, and the compounds disclosed in U.S. Pat. No.6,414,002; (i) anti-obesity agents, such as (1) growth hormonesecretagogues, growth hormone secretagogue receptoragonists/antagonists, such as NN703, hexarelin, MK-0677, SM-130686,CP-424,391, L-692,429, and L-163,255, and such as those disclosed inU.S. Pat. Nos. 5,536,716, and 6,358,951, U.S. Patent Application Nos.2002/049196 and 2002/022637, and PCT Application Nos. WO 01/56592 and WO02/32888; (2) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (3)cannabinoid receptor ligands, such as cannabinoid CB1 receptorantagonists or inverse agonists, such as rimonabant, taranabant,AMT-251, and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319(Solvay), BAY 65-2520 (Bayer) and those disclosed in U.S. Pat. Nos.5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736,5,624,941, 6,028,084, PCT Application Nos. WO 96/33159, WO 98/33765,WO98/43636, WO98/43635, WO 01/09120, WO98/31227, WO98/41519, WO98/37061,WO00/10967, WO00/10968, WO97/29079, WO99/02499, WO 01/58869, WO01/64632, WO 01/64633, WO 01/64634, WO02/076949, WO 03/007887, WO04/048317, and WO 05/000809; (4) anti-obesity serotonergic agents, suchas fenfluramine, dexfenfluramine, phentermine, and sibutramine; (5)β3-adrenoreceptor agonists, such as AD9677/TAK677 (Dainippon/Takeda),CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A,CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A; (6) pancreaticlipase inhibitors, such as orlistat (Xenical®), Triton WR¹³³⁹, RHC80267,lipstatin, tetrahydrolipstatin, teasaponin, diethylumbelliferylphosphate, and those disclosed in PCT Application No. WO 01/77094; (7)neuropeptide Y1 antagonists, such as BIBP3226, J-115814, BIBO 3304,LY-357897, CP-671906, GI-264879A, and those disclosed in U.S. Pat. No.6,001,836, and PCT Patent Publication Nos. WO 96/14307, WO 01/23387, WO99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (8)neuropeptide Y5 antagonists, such as GW-569180A, GW-594884A, GW-587081X,GW-548118X, FR²²⁶⁹²⁸, FR 240662, FR^(252384, 1229)U91, GI-264879A,CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104, andthose disclosed in U.S. Pat. Nos. 6,057,335; 6,043,246; 6,140,354;6,166,038; 6,180,653; 6,191,160; 6,313,298; 6,335,345; 6,337,332;6,326,375; 6,329,395; 6,340,683; 6,388,077; 6,462,053; 6,649,624; and6,723,847, European Patent Nos. EP-01010691, and EP-01044970; and PCTInternational Patent Publication Nos. WO 97/19682, WO 97/20820, WO97/20821, WO 97/20822, WO 97/20823, WO 98/24768; WO 98/25907; WO98/25908; WO 98/27063, WO 98/47505; WO 98/40356; WO 99/15516; WO99/27965; WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO01/14376; WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648; WO02/094825; WO 03/014083; WO 03/10191; WO 03/092889; WO 04/002986; and WO04/031175; (9) melanin-concentrating hormone (MCH) receptor antagonists,such as those disclosed in WO 01/21577 and WO 01/21169; (10)melanin-concentrating hormone 1 receptor (MCH1R) antagonists, such asT-226296 (Takeda), and those disclosed in PCT Patent Application Nos. WO01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO 02/076929, WO02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO 02/094799, WO03/004027; (11) melanin-concentrating hormone 2 receptor (MCH2R)agonist/antagonists; (12) orexin receptor antagonists, such asSB-334867-A, and those disclosed in patent publications herein; (13)serotonin reuptake inhibitors such as fluoxetine, paroxetine, andsertraline; (14) melanocortin agonists, such as Melanotan II; (15) Mc4r(melanocortin 4 receptor) agonists, such as CHIR⁸⁶⁰³⁶ (Chiron),ME-10142, and ME-10145 (Melacure), CHIR⁸⁶⁰³⁶ (Chiron); PT-141, and PT-14(Palatin); (16) 5HT-2 agonists; (17) 5HT2C (serotonin receptor 2C)agonists, such as BVT933, DPCA37215, WAY161503, R-1065, and thosedisclosed in U.S. Pat. No. 3,914,250, and PCT Application Nos. WO02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO02/51844, WO 02/40456, and WO 02/40457; (18) galanin antagonists; (19)CCK agonists; (20) CCK-A (cholecystokinin-A) agonists, such as AR-R15849, GI 181771, JMV-180, A-71378, A-71623 and SR14613, and thosedescribed in U.S. Pat. No. 5,739,106; (21) GLP-1 agonists; (22)corticotropin-releasing hormone agonists; (23) histamine receptor-3 (H3)modulators; (24) histamine receptor-3 (H3) antagonists/inverse agonists,such as hioperamide, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate,clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), andO-[3-(1H-imidazol-4-yl)propanol]-carbamates; (25) β-hydroxy steroiddehydrogenase-1 inhibitors (β-HSD-1); (26) PDE (phosphodiesterase)inhibitors, such as theophylline, pentoxifylline, zaprinast, sildenafil,amrinone, milrinone, cilostamide, rolipram, and cilomilast; (27)phosphodiesterase-3B (PDE3B) inhibitors; (28) NE (norepinephrine)transport inhibitors, such as GW 320659, despiramine, talsupram, andnomifensine; (29) ghrelin receptor antagonists, such as those disclosedin PCT Application Nos. WO 01/87335, and WO 02/08250; (30) leptin,including recombinant human leptin (PEG-0B, Hoffman La Roche) andrecombinant methionyl human leptin (Amgen); (31) leptin derivatives;(32) BRS3 (bombesin receptor subtype 3) agonists such as[D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and[D-Phe6,Phe13]Bn(6-13)propylamide, and those compounds disclosed inPept. Sci. 2002 August; 8(8): 461-75); (33) CNTF (Ciliary neurotrophicfactors), such as GI-181771 (Glaxo-SmithKline), SR¹⁴⁶¹³¹ (SanofiSynthelabo), butabindide, PD170,292, and PD 149164 (Pfizer); (34) CNTFderivatives, such as axokine (Regeneron); (35) monoamine reuptakeinhibitors, such as sibutramine; (36) UCP-1 (uncoupling protein-1), 2,or 3 activators, such as phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), retinoic acid; (37) thyroid hormone 13 agonists, such asKB-2611 (KaroBioBMS); (38) FAS (fatty acid synthase) inhibitors, such asCerulenin and C75; (39) DGAT1 (diacylglycerol acyltransferase 1)inhibitors; (40) DGAT2 (diacylglycerol acyltransferase 2) inhibitors;(41) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (42) glucocorticoidantagonists; (43) acyl-estrogens, such as oleoyl-estrone, disclosed indel Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); (44)dipeptidyl peptidase IV (DP-IV) inhibitors, such as isoleucinethiazolidide, valine pyrrolidide, NVP-DPP728, LAF237, P93/01, TSL 225,TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, SDZ 274-444, sitagliptin;and the compounds disclosed in U.S. Pat. No. 6,699,871, WO 03/004498; WO03/004496; EP 1 258 476; WO 02/083128; WO 02/062764; WO 03/000250; WO03/002530; WO 03/002531; WO 03/002553; WO 03/002593; WO 03/000180; andWO 03/000181; (46) dicarboxylate transporter inhibitors; (47) glucosetransporter inhibitors; (48) phosphate transporter inhibitors; (49)Metformin (Glucophage®); (50) Topiramate (Topimax®); (50) peptide YY,PYY 3-36, peptide YY analogs, derivatives, and fragments such asBIM-43073D, BIM-43004C (Olitvak, D. A. et al., Dig. Dis. Sci.44(3):643-48 (1999)); (51) Neuropeptide Y2 (NPY2) receptor agonists suchNPY3-36, N acetyl [Leu(28,31)] NPY 24-36, TASP-V, andcyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) Neuropeptide Y4 (NPY4)agonists such as pancreatic peptide (PP), and other Y4 agonists such as1229U91; (54) cyclooxygenase-2 inhibitors such as etoricoxib, celecoxib,valdecoxib, parecoxib, lumiracoxib, BMS347070, tiracoxib or JTE522,ABT963, CS502 and GW406381; (55) Neuropeptide Y1 (NPY1) antagonists suchas BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (56)Opioid antagonists such as nalmefene (Revex®), 3-methoxynaltrexone,naloxone, naltrexone; (57) 1113 HSD-1 (11-beta hydroxy steroiddehydrogenase type 1) inhibitors such as BVT 3498, BVT 2733, and thosedisclosed in WO 01/90091, WO 01/90090, WO 01/90092, U.S. Pat. No.6,730,690 and US 2004-0133011; (58) aminorex; (59) amphechloral; (60)amphetamine; (61) benzphetamine; (62) chlorphentermine; (63)clobenzorex; (64) cloforex; (65) clominorex; (66) clortermine; (67)cyclexedrine; (68) dextroamphetamine; (69) diphemethoxidine,(70)N-ethylamphetamine; (71) fenbutrazate; (72) fenisorex; (73)fenproporex; (74) fludorex; (75) fluminorex; (76)furfurylmethylamphetamine; (77) levamfetamine; (78) levophacetoperane;(79) mefenorex; (80) metamfepramone; (81) methamphetamine; (82)norpseudoephedrine; (83) pentorex; (84) phendimetrazine; (85)phenmetrazine; (86) picilorex; (87) phytopharm 57; and (88) zonisamide.,(89) neuromedin U and analogs or derivatives thereof, (90) oxyntomodulinand analogs or derivatives thereof, and (91) Neurokinin-1 receptorantagonists (NK-1 antagonists) such as the compounds disclosed in: U.S.Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595,5,459,270, 5,494,926, 5,496,833, and 5,637,699.

In another embodiment, the subject compound may be employed incombination with an anti-depressant or anti-anxiety agent, includingnorepinephrine reuptake inhibitors (including tertiary amine tricyclicsand secondary amine tricyclics), selective serotonin reuptake inhibitors(SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors ofmonoamine oxidase (RIMAs), serotonin and noradrenaline reuptakeinhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists,atypical anti-depressants, benzodiazepines, 5-HT_(1A) agonists orantagonists, especially 5-HT_(1A) partial agonists, and corticotropinreleasing factor (CRF) antagonists. Specific agents include:amitriptyline, clomipramine, doxepin, imipramine and trimipramine;amoxapine, desipramine, maprotiline, nortriptyline and protriptyline;citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine andsertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline;moclobemide: venlafaxine; aprepitant; bupropion, lithium, nefazodone,trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam,chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam;buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceuticallyacceptable salts thereof

In another embodiment, the subject compound may be employed incombination with anti-Alzheimer's agents; beta-secretase inhibitors;gamma-secretase inhibitors; growth hormone secretagogues; recombinantgrowth hormone; HMG-CoA reductase inhibitors; NSAID's includingibuprofen; vitamin E; anti-amyloid antibodies; CB-1 receptor antagonistsor CB-1 receptor inverse agonists; antibiotics such as doxycycline andrifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such asmemantine; cholinesterase inhibitors such as galantamine, rivastigmine,donepezil, and tacrine; growth hormone secretagogues such as ibutamoren,ibutamoren mesylate, and capromorelin; histamine H3 antagonists; AMPAagonists; PDE IV inhibitors; GABAA inverse agonists; or neuronalnicotinic agonists.

In another embodiment, the subject compound may be employed incombination with sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, cyclopyrrolones, imidazopyridines,pyrazolopyrimidines, minor tranquilizers, melatonin agonists andantagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2antagonists, and the like, such as: adinazolam, allobarbital, alonimid,alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam,benzoctamine, brotizolam, bupropion, busprione, butabarbital,butalbital, capuride, carbocloral, chloral betaine, chloral hydrate,chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate,clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam,ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam,fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam,hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline,mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone,midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital,sertraline, suproclone, temazepam, thioridazine, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, andcombinations thereof, and the like, or the subject compound may beadministered in conjunction with the use of physical methods such aswith light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole.

In another embodiment, the subject compound may be employed incombination with acetophenazine, alentemol, benzhexol, bromocriptine,biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam,fenoldopam, fluphenazine, haloperidol, levodopa, levodopa withbenserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine,molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide,pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl,thioridazine, thiothixene or trifluoperazine.

In another embodiment, the subject compound may be employed incombination with a compound from the phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine andindolone classes of neuroleptic agent. Suitable examples ofphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitableexamples of thioxanthenes include chlorprothixene and thiothixene. Anexample of a dibenzazepine is clozapine. An example of a butyrophenoneis haloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone.

In another embodiment, the subject compound may be employed incombination with a nicotine agonist or a nicotine receptor partialagonist such as varenicline, opioid antagonists (e.g., naltrexone(including naltrexone depot), antabuse, and nalmefene), dopaminergicagents (e.g., apomorphine), ADD/ADHD agents (e.g., methylphenidatehydrochloride (e.g., Ritalin® and Concerta®), atomoxetine (e.g.,Strattera®), a monoamine oxidase inhibitor (MAOI), amphetamines (e.g.,Adderall®)) and anti-obesity agents, such as apo-B/MTP inhibitors,11Beta-hydroxy steroid dehydrogenase-1 (11Beta-HSD type 1) inhibitors,peptide YY3-36 or analogs thereof, MCR-4 agonists, CCK-A agonists,monoamine reuptake inhibitors, sympathomimetic agents, β3 adrenergicreceptor agonists, dopamine receptor agonists, melanocyte-stimulatinghormone receptor analogs, 5-HT2c receptor agonists, melaninconcentrating hormone receptor antagonists, leptin, leptin analogs,leptin receptor agonists, galanin receptor antagonists, lipaseinhibitors, bombesin receptor agonists, neuropeptide-Y receptorantagonists (e.g., NPY Y5 receptor antagonists), thyromimetic agents,dehydroepiandrosterone or analogs thereof, glucocorticoid receptorantagonists, other orexin receptor antagonists, glucagon-like peptide-1receptor agonists, ciliary neurotrophic factors, human agouti-relatedprotein antagonists, ghrelin receptor antagonists, histamine 3 receptorantagonists or inverse agonists, and neuromedin U receptor agonists, andpharmaceutically acceptble salts thereof

In another embodiment, the subject compound may be employed incombination with an anoretic agent such as aminorex, amphechloral,amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex,clominorex, clortermine, cyclexedrine, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex and sibutramine; selectiveserotonin reuptake inhibitor (SSRI); halogenated amphetaminederivatives, including chlorphentermine, cloforex, clortermine,dexfenfluramine, fenfluramine, picilorex and sibutramine; andpharmaceutically acceptble salts thereof

In another embodiment, the subject compound may be employed incombination with an opiate agonist, a lipoxygenase inhibitor, such as aninhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as acyclooxygenase-2 inhibitor, an interleukin inhibitor, such as aninterleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalantiinflammatory agent, or a cytokine-suppressing antiinflammatoryagent, for example with a compound such as acetaminophen, asprin,codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine,naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl,sunlindac, tenidap, and the like. Similarly, the subject compound may beadministered with a pain reliever; a potentiator such as caffeine, anH2-antagonist, simethicone, aluminum or magnesium hydroxide; adecongestant such as phenylephrine, phenylpropanolamine, pseudophedrine,oxymetazoline, ephinephrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such ascodeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; adiuretic; and a sedating or non-sedating antihistamine.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention may beeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. Compositions for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin, or olive oil. Aqueous suspensions contain the active materialsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Oily suspensions may be formulated by suspending the activeingredient in a suitable oil. Oil-in-water emulsions may also beemployed. Dispersible powders and granules suitable for preparation ofan aqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Pharmaceutical compositions of thepresent compounds may be in the form of a sterile injectable aqueous oroleagenous suspension. The compounds of the present invention may alsobe administered in the form of suppositories for rectal administration.For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention may be employed.The compounds of the present invention may also be formulated foradministered by inhalation. The compounds of the present invention mayalso be administered by a transdermal patch by methods known in the art.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art (e.g. PCT PatentPublications WO2001/68609, WO2004/085403, WO2005/118548, WO2008/147518,WO2009/143033 and WO2010/048012) or as illustrated herein. The followingabbreviations are used herein: Me: methyl; Et: ethyl; t-Bu: tert-butyl;Ar: aryl; Ph: phenyl; Bn: benzyl; Ac: acetyl; Boc: tert-butyloxycarbonyl; BSA: bovine serum albumin; CbzCl: benzylchloroformate; CDI:carbonyl diimidazole; DCM: dichloromethane; DCE: dichloroethane; DEAD:diethylazodicarboxylate; DIPEA: N,N-diisopropylethylamine; DMF:N,N-dimethylformamide; DMSO: dimethylsulfoxide; CH₂Cl₂: dichloromethane;EDC: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide; Et₃N:triethylamine; EtOAc: ethylacetate; EtOH: ethanol; HCl: hydrogenchloride; HOAt: 1-hydroxy-7-aza-benzotriazole; HOBT:hydroxybenzotriazole hydrate; HPLC: high performance liquidchromatography; Hunig's base: N,N-diisopropylethylamine; MeOH: methanol;MgSO₄: magnesium sulfate; MTBE: methyl tert-butyl ether; NaHCO₃: sodiumbicarbonate; NaOH: sodium hydroxide; NMM: N-methylmorpholine; PyClu:1-(chloro-1-pyrrolidinylmethylene)-pyrrolidinium hexafluorophosphate;rt: room temperature; SOCl₂: thionyl chloride; T3P:2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide; THF:tetrahydrofuran; TFA: trifluoracetic acid. The compounds of the presentinvention can be prepared in a variety of fashions.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart. In some cases the order of carrying out the foregoing reactionschemes may be varied to facilitate the reaction or to avoid unwantedreaction products. The following examples are provided so that theinvention might be more fully understood. These examples areillustrative only and should not be construed as limiting the inventionin any way.

Example 1

2-(((3R,6R)-1-(2-(2H-1,2,3-Triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)amino)isonicotinonitrileStep 1: (2R,5S)-Benzyl2-methyl-5-((methylsulfonyl)oxy)piperidine-1-carboxylate (2)

A solution of (2R,5S)-benzyl 5-hydroxy-2-methylpiperidine-1-carboxylate(15.0 g, 60.2 mmol), 4-dimethylamino pyridine (0.74 g, 6.0 mmol), andCH₂Cl₂ (401 mL) was treated with DIEA (15.8 mL, 90.0 mmol) and cooled at0° C. Methanesulfonyl chloride (5.9 mL, 75 mmol) in CH₂Cl₂ (67 mL) wasadded dropwise and stirring continued at 0° C. for 2 h. The reaction wasdiluted with water and 1 N HCl and the separated organics were washedwith brine, dried over MgSO₄, filtered, concentrated and dried,providing the crude title compound which was used without furtherpurification. LRMS m/z (M+H) 328.3 found, 328.1 required.

Step 2: (2R,5R)-Benzyl 5-azido-2-methylpiperidine-1-carboxylate (3)

A solution of crude (2R,5S)-benzyl2-methyl-5-((methylsulfonyl)oxy)piperidine-1-carboxylate (19.7 g, 60.2mmol) and sodium azide (6.65 g, 102 mmol) in DMF (86 mL) was heated to85° C. overnight. The reaction was diluted with EtOAc, washed 2× withwater, 1× with brine, dried over magnesium sulfate, filtered, andconcentrated, providing the crude title compound which was used withoutfurther purification. LRMS m/z (M+H) 275.3 found, 275.2 required.

Step 3: (2R,5R)-Benzyl 5-amino-2-methylpiperidine-1-carboxylate (4)

To a solution of (2R,5R)-benzyl 5-azido-2-methylpiperidine-1-carboxylate(15.2 g, 55.4 mmol) in THF (111 mL) was added trimethylphosphine (1.0 Min toluene, 55.4 mL, 55.4 mmol) dropwise over 20 min. The reaction wasquenched with water (30 mL) and stirred at RT overnight. The mixture wasdiluted with dichloromethane, washed 2× with water, 1× with brine, driedover magnesium sulfate, filtered, and concentrated, providing the crudetitle compound as an orange oil which was used without furtherpurification. LRMS m/z (M+H) 249.6 found, 249.3 required.

Step 4:(2R,5R)-Benzyl-5-((tert-butoxycarbonyl)amino-2-methylpiperidine-1-carboxylate(5)

A solution of (2R,5R)-Benzyl 5-amino-2-methylpiperidine-1-carboxylate(3.08 g, 12.4 mmol) and 4-dimethylaminopyridine (0.015 g, 0.12 mmol) indichloromethane (62 mL) was treated with a solution of di-tert-butyldicarbonate (2.91 mL, 12.5 mmol) in dichloromethane (20 mL) dropwise andstirred at RT overnight. The reaction was concentrated in vacuo,providing the crude title compound which was used without furtherpurification. LRMS m/z (M+H) 349.4 found, 349.3 required.

Step 5: tert-Butyl ((3R,6R)-6-methylpiperidin-3-yl)carbamate (6)

A solution of(2R,5R)-benzyl-5-((tert-butoxycarbonyl)amino-2-methylpiperidine-1-carboxylate(4.32 g, 12.4 mmol) and palladium (10 wt % on activated carbon, 0.300 g,2.82 mmol) in degassed ethanol (100 mL) and methanol (5 mL) was stirredfor 72 h under an atmosphere of hydrogen gas. Additional palladium (10wt % on activated carbon, 0.10 g, 0.94 mmol) was added, and the reactionwas recharged with hydrogen gas and allowed to stir at RT overnight. Thedegassed mixture was then filtered over celite, washing with EtOH. Thefiltrate was concentrated to give the titled compound as a crude, lightyellow solid which was used without further purification.

Step 6:tert-Butyl((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)carbamate(7)

A solution of 2-(2H-1,2,3-triazol-2-yl)benzoic acid (4.24 g, 22.40mmol), tert-butyl ((3R,6R)-6-methylpiperidin-3-yl)carbamate (3.20 g,14.93 mmol), 1-hydroxy-7-azabenzotriazole (4.06 g, 29.9 mmol), EDC (5.72g, 29.9 mmol), and DIEA (15.65 mL, 90 mmol) in DMF (100 mL) was heatedat 50° C. overnight. The reaction was diluted with saturated, aqu.NaHCO₃ and extracted 2× with EtOAc. The organics were washed with brine,dried over MgSO₄, filtered, and concentrated. The residue was purifiedby silica gel gradient chromatography (0-80% EtOAc in hexanes),providing the title compound. LRMS m/z (M+H) 386.4 found, 386.2required.

Step 7:(2-(2H-1,2,3-Triazol-2-yl)phenyl)((2R,5R)-5-amino-2-methylpiperidin-1-yl)methanone(8)

A solution oftert-butyl((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)carbamate(3.6 g, 9.3 mmol) in EtOAc (78 mL) was saturated with HCl (g) andstirred for 2 h. The reaction was concentrated and the residue basifiedwith 1 N NaOH. The mixture was extracted 3× with EtOAc, then theorganics were washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by silica gel gradientchromatography (0-20% MeOH in CH₂Cl₂), providing the title compound.LRMS m/z (M+H) 286.3 found, 286.3 required.

Step 8:2-(((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)amino)isonicotinonitrile

A solution of(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-amino-2-methylpiperidin-1-yl)methanone(400 mg, 1.40 mmol) 2-fluoroisonicotinonitrile (342 mg, 2.80 mmol), andcesium carbonate (776 mg, 2.383 mmol) in DMSO (4673 μL) was heated at50° C. for 48 h. The reaction was cooled, diluted with water andsaturated aqueous sodium bicarbonate, and extracted 2× with EtOAc. Thecombined organic fractions were washed with brine, dried over magnesiumsulfate, filtered, and concentrated. The residue was purified by silicagel gradient chromatography (0-50% EtOAc in hexanes), providing thetitle compound. LRMS m/z (M+H) 388.4 found, 388.2 required.

TABLE 1 The following compound was prepared using the foregoingmethodology and general procedure described in Example 1, butsubsitituting the appropriate electrophile for2-fluoroisonicotinonitrile (Step 8), as described in the foregoingReaction Schemes and Examples. The requisite starting materials werecommercially available, described in the literature or readilysynthesized by one skilled in the art of organic synthesis fromcommerically available reagents using conventional reactions withoutundue experimentation. Example Structure Name HRMS 2

3-methoxy-2-{[(3R,6R)-6- methyl-1-{[2-(2H-1,2,3- triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl]amino}pyridine-4- carbonitrileC₂₂H₂₃N₇O₂ [M + H] Calc'd 418.1988, found 418.1970

Example 3

2-(((3R,6R)-1-(2-(2H-Tetrazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)amino)isonicotinonitrileStep 1: (2R,5R)-benzyl5-((4-cyanopyridin-2-yl)amino)-2-methylpiperidine-1-carboxylate (9)

A solution of (2R,5R)-benzyl 5-amino-2-methylpiperidine-1-carboxylate(150 mg, 0.604 mmol), 2-fluoroisonicotinonitrile (148 mg, 1.208 mmol),and cesium carbonate (335 mg, 1.027 mmol) in DMSO (2 mL) was heated at80° C. overnight. The reaction was cooled, diluted with water andsaturated aqueous sodium bicarbonate, and extracted 2× with EtOAc. Thecombined organic fractions were washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified by silica gelgradient chromatography (0-25% EtOAc in hexanes), providing the titlecompound. LRMS m/z (M+H) 351.4 found, 351.2 required.

Step 2: 2-(((3R,6R)-6-methylpiperidin-3-yl)amino)isonicotinonitrile (10)

A solution of (2R,5R)-benzyl5-((4-cyanopyridin-2-yl)amino)-2-methylpiperidine-1-carboxylate (89 mg,0.254 mmol) in CH₂Cl₂ (5.0 mL) was treated, at RT, with dimethylsulfide(507 μL, 6.86 mmol), then boron trifluoride etherate (321 μL, 1.22mmol). After stirring overnight, the reaction was poured into 10% aqu.NH₄OH and extracted 2× with CH₂Cl₂. The combined organic fractions werewashed with brine, dried over MgSO₄, filtered, and concentrated,providing the crude title compound. LRMS m/z (M+H) 217.2 found, 217.1required.

Step 3:2-(((3R,6R)-1-(2-(2H-tetrazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)amino)isonicotinonitrile

A solution of2-(((3R,6R)-6-methylpiperidin-3-yl)amino)isonicotinonitrile (55 mg,0.254 mmol), 2-(2H-tetrazol-2-yl)benzoic acid (58.0 mg, 0.305 mmol),1-hydroxy-7-azabenzotriazole (69.2 mg, 0.509 mmol), and EDC (97 mg,0.509 mmol) in DMF (2.5 mL) was treated with DIEA (266 μL, 1.526 mmol)and heated at 50° C. overnight. The reaction was cooled, diluted withwater and saturated aqueous NaHCO₃, and extracted 2× with EtOAc. Thecombined organic fractions were washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified by silica gelgradient chromatography (0-85% EtOAc in hexanes), providing the titlecompound. HRMS m/z (M+H) 389.1818 found, 389.1833 required.

Example 4

2-(((3R,6R)-1-(2-(2H-1,2,3-Triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)amino)-3-methylisonicotinonitrileStep 1: (2R,5R)-benzyl5-((4-cyano-3-methylpyridin-2-yl)amino)-2-methylpiperidine-1-carboxylate(11)

Prepared as per Example 3, Step 1, substituting2-fluoro-3-methylisonicotinonitrile as the electrophile. The residue waspurified by silica gel gradient chromatography (0-70% EtOAc in hexanes),providing the title compound. LRMS m/z (M+H) 365.4 found, 365.2required.

Step 2:3-methyl-2-(((3R,6R)-6-methylpiperidin-3-yl)amino)isonicotinonitrile(12)

A solution of (2R,5R)-benzyl5-((4-cyano-3-methylpyridin-2-yl)amino)-2-methylpiperidine-1-carboxylate(31 mg, 0.085 mmol) in EtOH (1.7 mL) was evacuated 4× and backfilledwith nitrogen each time. Palladium on carbon (6.3 mg, 6.0 μmol) wasadded, and the reaction was evacuated and backfilled 2× from a hydrogenballoon. After stirring overnight, additional palladium on carbon wasadded and the reaction was again purged with hydrogen, and stirringcontinued for several more hours. The reaction was evacuated andbackfilled with nitrogen, then diluted with EtOH and filtered throughCelite. The filtrated was concentrated and dried to provide the titlecompound. LRMS m/z (M+H) 231.3 found, 231.2 required.

Step 3:2-(((3R,6R)-1-(2-(2H-1,2,3-Triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)amino)-3-methylisonicotinonitrile

Prepared as per Example 3, Step 3, substituting2-(2H-1,2,3-triazol-2-yl)benzoic acid as the carboxylic acid. Theresidue was purified by silica gel gradient chromatography (0-65% EtOAcin hexanes), then further purified by reversed-phase chromatography(10-75% MeCN in H₂O, 0.1% TFA), providing the title compound. HRMS m/z(M+H) 402.2024 found, 402.2037 required.

TABLE 2 The following compound was prepared using the foregoingmethodology and general procedure described in Example 4, substitutingthe appropriate carboxylic acid for 2-(2H-1,2,3-triazol-2-yl)benzoicacid (Step 3), as described in the foregoing Reaction Schemes andExamples. The requisite starting materials were commerically available,described in the literature or readily synthesized by one skilled in theart of organic synthesis from commerically available reagents usingconventional reactions without undue experimentation. Example StructureName HRMS 5

3-methyl-2-{[(3R,6R)- 6-methyl-1-{[2-(2H- tetrazol-2-yl)phenyl]-carbonyl}-piperidin-3- yl]amino}pyridine-4- carbonitrile C₂₁H₂₂N₈O [M +H] Calc'd 403.1992, found 403.1979

Example 6

2-((3R,6R)-1-(2-(2H-1,2,3-Triazol-2-yl)thiophene-3-carbonyl)-6-methylpiperidin-3-ylamino)-3-methoxyisonicotinonitrileStep 1: (2R,5R)-benzyl5-(4-cyano-3-methoxypyridin-2-ylamino)-2-methylpiperidine-1-carboxylate

A mixture of 5-amino-2-methyl-piperidine-1-carboxylic acid benzyl ester(800 mg, 3.22 mmol), 2-chloro-3-methoxy-isonicotinonitrile (815 mg, 4.83mmol), Pd(dppf)Cl₂ (235 mg, 0.32 mmol) and NaOtBu (618 mg, 6.44 mmol) inanhydrous THF (100 mL) was heated at 80° C. with stirring under nitrogenfor 16 hr. The mixture was cooled to room temperature and concentratedin vacuo. The residue was purified by column chromatography (0-12.5%ethyl acetate in petroleum ether), providing the title compound asyellow oil. LRMS m/z (M+H) 381.2 found, 381.18 required.

Step 2:2-((3R,6R)-6-methylpiperidin-3-ylamino)-3-methoxypyridine-4-carbonitrile

To a solution of (2R,5R)-benzyl5-(4-cyano-3-methoxypyridin-2-ylamino)-2-methylpiperidine-1-carboxylate(350 mg, 0.92 mmol) in MeOH (25 mL) was added Pd/C (10%, 100 mg) at roomtemperature. The resulting mixture was stirred under hydrogen for 1 h.The mixture was filtered and the filtrate was concentrated in vacuo,providing the title compound as yellow oil. LRMS m/z (M+H) 247.2 found,247.15 required

Step 3:2-(((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)thiophene-3-carbonyl)-6-methylpiperidin-3-yl)amino)-3-methoxyisonicotinonitrile

To a solution of2-((3R,6R)-6-methylpiperidin-3-ylamino)-3-methoxypyridine-4-carbonitrile(45 mg, 0.18 mmol) in anhydrous dichloromethane (20 mL) was addedtriethylamine (28 mg, 0.28 mmol) at ˜5° C. After stirring for 15 min, asolution of 2-[1,2,3]triazol-2-yl-thiophene-3-carbonyl chloride(prepared from 48.8 mg of 2-[1,2,3]triazol-2-yl-thiophene-3-carboxylicacid) in anhydrous CH₂Cl₂ (5 mL) was added via syringe at ˜5° C. Theresulting mixture was stirred at 25° C. for 16 h. The mixture wasconcentrated in vacuo and purified by prep TLC (50% ethyl acetate inpetroleum ether), providing the title compound as pale white solid. LRMSm/z (M+H) 424.2 found, 424.15 required.

TABLE 3 The following compound was prepared using the foregoingmethodology and general procedure described in Example 6, substitutingthe appropriate acid for 2-(2H-1,2,3-triazol-2-yl)thiophene-3-carboxylic acid (Step 3), as described in the foregoing Reaction Schemesand Examples. The requisite starting materials were commerciallyavailable, described in the literature or readily synthesized by oneskilled in the art of organic synthesis from commerically availablereagents using conventional reactions without undue experimentation.Example Structure Name LRMS 7

3-methoxy-2-((3R,6R)-6- methyl-1-(2-(pyrimidin-2- yl)thiophene-3-carbonyl)piperidin-3- ylamino)isonicotinonitrile C₂₂H₂₂N₆O₂S [M + H]calc 435.15 obs 435.1

Example 8

2-(((3R,6R)-1-(2-(2H-1,2,3-Triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)(methyl)amino)isonicotinonitrile

A solution of2-(((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)amino)isonicotinonitrile(Example 1, 8.3 mg, 0.021 mmol) in DMF (1 mL) was treated with sodiumhydride (0.5 mg, 0.02 mmol) at RT. After a few mins, iodomethane (1.3μL, 0.021 mmol) was added. After 30 mins, additional NaH and iodomethanewere added to complete the conversion. The reaction was quenched withH₂O, then diluted with saturated aqueous NaHCO₃, and extracted 2× withEtOAc. The combined organic fractions were washed with brine, dried overMgSO₄, filtered, and concentrated. The residue was purified byreversed-phase chromatography (10-80% MeCN in H₂O, 0.1% TFA), providingthe title compound. HRMS Miz (M+H) 402.2048 found, 402.2037 required.

TABLE 4 The following compounds were prepared using the foregoingmethodology and general procedure described in Example 8, substitutingthe appropriate alkyl halide for iodomethane, as described in theforegoing Reaction Schemes and Examples. The requisite startingmaterials were commercially available, described in the literature orreadily synthesized by one skilled in the art of organic synthesis fromcommercially available reagents using conventional reactions withoutundue experimentation. Example Structure Name LRMS/HRMS  9

2-{methyl[(3R,6R)-6- methyl-1-{[2-(2H- tetrazol-2-yl)phenyl]-carbonyl}piperidin-3- yl]amino}pyridine-4- carbonitrile C₂₁H₂₂N₈O [M +H] Calc'd 403.1989, found 403.1986 10

3-methoxy-2- {methyl[(3R,6R)-6- methyl-1-{[2-(2H-1,2,3-triazol-2-yl)thiophen-3- yl]carbonyl}piperidin-3- yl]amino}pyridine-4-carbonitrile C₂₁H₂₄N₇O₂S [M + H] Calc'd 438.2, found 438.2 11

3-methoxy-2- (methyl{(3R,6R)-6- methyl-1-[(2-pyrimidin- 2-ylthiophen-3-yl)carbonyl]piperidin-3- yl}amino)pyridine-4- carbonitrile C₂₃H₂₄N₆O₂S[M + H] calc 449.17 found 449.2 12

2-{ethyl[(3R,6R)-6- methyl-1-{[2-(2H-1,2,3- triazol-2-yl)phenyl]carbonyl} piperidin-3-yl]amino}- pyridine-4-carbonitrileC₂₃H₂₅N₇O [M + H] Calc'd 416.2200, found 416.2193 13

2-{[(3R,6R)-6-methyl-1- {[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin- 3-yl](prop-2-en-1- yl)amino}pyridine-4-carbonitrile C₂₄H₂₅N₇O [M + H] Calc'd 428.2193, found 428.2193 14

2-{[(3R,6R)-6-methyl-1- {[2-(2H-1,2,3-triazol-2- yl)phenyl]carbonyl}piperidin-3-yl](propyl)- amino}pyridine-4- carbonitrile C₂₄H₂₇N₇O [M +H] Calc'd 430.2350, found 430.2338

Example 15

N-((3R,6R)-1-(2-(2H-1,2,3-Triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)-N-(4-cyanopyridin-2-yl)acetamide

A solution of2-(((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)amino)isonicotinonitrile(35 mg, 0.090 mmol) in CH₂Cl₂ (900 μL) was treated with DIEA (79 μL,0.45 mmol) and acetyl chloride (16 μL, 0.23 mmol) at RT. After stirringovernight, additional DIEA and acetyl chloride were added and thereaction was heated at 35° C. for 8 h. The reaction was quenched byaddition of saturated, aqu. NH₄Cl, then diluted with saturated aqueousNaHCO₃, and extracted 2× with EtOAc. The combined organic fractions werewashed with brine, dried over MgSO₄, filtered, and concentrated. Theresidue was purified by silica gel gradient chromatography (0-100% EtOAcin hexanes), providing the title compound. HRMS m/z (M+H) 403.1979found, 403.1986 required.

The following table shows representative data for the compounds of theExamples as orexin receptor antagonists as determined by the foregoingassays wherein the hOX2R Ki is a measure of the ability of the testcompound to inhibit the action of the human orexin-2 receptor and thehOX1R Ki is a measure of the ability of the test compound to inhibit theaction of the rat orexin-1 receptor. The following table showsrepresentative data for the compounds of the Examples as orexin receptorantagonists as determined by the assays herein.

hOX2R FLIPR hOX1R FLIPR Example IC₅₀ (nM) IC₅₀ (nM) 1 29 1742 2 11 267 39 1922 4 7 745 5 7 1149 6 11 827 7 47 384 8 20 2048 9 32 2236 1039 >10,000 11 34 >10,000 12 23 1990 13 23 2548 14 13 330 15 1781 >10,000

With respect to other piperidine compounds such as those disclosed in WO2010/048012, it would be desirable that the present compounds exhibitunexpected properties, such as increased selectivity at the orexin-2receptor relative to the orexin-1 receptor. For example, relative tocertain compounds of WO2010/048012 that do not possess a2-pyridylthio-piperidine, the compounds of the examples possess greaterselectivity for the orexin-2 receptor than for the orexin-1 receptor.

For example, the following compounds are disclosed in WO 2010/048012:

Representative compounds herein are the compounds of Example 1, 3 and 4.

As indicated by the data herein, the compounds of the present examplesprovide greater functional selectivity for the orexin-2 receptor overthe orexin-1 receptor. The distinction in potency between the orexin-2receptor and the orexin-1 receptor in the whole cell FLIPR functionalassay provides enhanced predictive value for determining in vivoefficacy. Increasing the functional selectivity for the orexin-2receptor reduces the potential for dual receptor antagonism in vivo.Such greater functional selectivity may provide benefits over otherorexin receptor antagonists that are known in the art.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

1. A compound of the formula I:

wherein: A is selected from the group consisting of phenyl, naphthyl andheteroaryl; R^(1a), R^(1b) and R^(1c) are independently selected fromthe group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4)—(C═O)_(m)—O_(n)—C₁₋₆ alkyl, where m is 0 or 1, n is 0 or 1 (wherein ifm is 0 or n is 0, a bond is present) and where the alkyl isunsubstituted or substituted with one or more substituents selected fromR⁴, (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl isunsubstituted or substituted with one or more substituents selected fromR⁴, (6) —(C═O)_(m)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted orsubstituted with one or more substituents selected from R⁴, (7)—(C═O)_(m)—C₂₋₄ alkynyl, where the alkynyl is unsubstituted orsubstituted with one or more substituents selected from R⁴, (8)—(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-naphthyl, where the phenylor naphthyl is unsubstituted or substituted with one or moresubstituents selected from R⁴, (9) —(C═O)_(m)—O_(n)-heterocycle, wherethe heterocycle is unsubstituted or substituted with one or moresubstituents selected from R⁴, (10) —(C═O)_(m)—NR¹⁰R¹¹, wherein R¹⁰ andR¹¹ are independently selected from the group consisting of: (a)hydrogen, (b) C₁₋₆alkyl, which is unsubstituted or substituted with R⁴,(c) C₃₋₆alkenyl, which is unsubstituted or substituted with R⁴, (d)C₃₋₆alkynyl, which is unsubstituted or substituted with R⁴, (e)C₃₋₆cycloalkyl which is unsubstituted or substituted with R⁴, (f)phenyl, which is unsubstituted or substituted with R⁴, and (g)heterocycle, which is unsubstituted or substituted with R⁴, (11)—S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹²is selected from the definitions of R¹⁰ and R¹¹, (13) —CO₂H, (14) —CN,and (15) —NO₂; R³ is selected from C₁₋₆alkyl and C₃₋₆cycloalkyl, whichis unsubstituted or substituted with one or more substituents selectedfrom R⁴; R⁴ is selected from the group consisting of: (1) hydroxyl, (2)halogen, (3) C₁₋₆ alkyl, (4) —C₃₋₆cycloalkyl, (5) —O—C₁₋₆alkyl, (6)—O(C═O)—C₁₋₆ alkyl, (7) —NH₂, (7) —NH—C₁₋₆ alkyl, (8) —NO₂, (9) phenyl,(10) heterocycle, (11) —CO₂H, and (12) —CN; R⁵ is selected from thegroup consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C₁₋₆alkyl, which is unsubstituted or substituted with halogen, hydroxyl orphenyl, (5) C₃₋₆ cycloalkyl, which is unsubstituted or substituted withC₁₋₆ alkyl, halogen, hydroxyl or phenyl, (6) —O—C₁₋₆ alkyl, which isunsubstituted or substituted with halogen, hydroxyl or phenyl, and (7)—S—C₁₋₆ alkyl, which is unsubstituted or substituted with halogen,hydroxyl or phenyl; R⁶ is selected from the group consisting of: (1)hydrogen, (2) C₁₋₆ alkyl, which is unsubstituted or substituted withoxo, halogen, hydroxyl or phenyl, (3) C₂₋₆ alkenyl, and (4) —(CO)—O—C₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 2. The compound ofclaim 1 of the formula Ia:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1 of the formula Ia′:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1 of the formula Ib:

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1 or a pharmaceutically acceptable salt thereof wherein A is selectedfrom phenyl, pyridyl, thiophenyl, thiazolyl, isothiazolyl, andpyrazolyl.
 6. The compound of claim 1 or a pharmaceutically acceptablesalt thereof wherein R^(1a), R^(1b) and R^(1c) are independentlyselected from the group consisting of: (1) hydrogen, (2) halogen, (3)hydroxyl, (4) C₁₋₆ alkyl, which is unsubstituted or substituted withhalogen, hydroxyl or phenyl, (5) —O—C₁₋₆alkyl, which is unsubstituted orsubstituted with halogen, hydroxyl or phenyl, (6) —CN, and (7)heteroaryl, wherein heteroaryl is selected from triazolyl, tetrazolyl,oxazolyl, pyrrolyl, imidazolyl, indolyl, pyridyl, and pyrimidinyl, whichis unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,—O—C₁₋₆alkyl or —NO₂.
 7. The compound of claim 6 or a pharmaceuticallyacceptable salt thereof wherein R^(1c) is hydrogen, and R^(1a) andR^(1b) are independently selected from the group consisting of: (1)hydrogen, (2) fluoro, (3) chloro, (4) bromo, (5) methyl, (6) ethyl, (7)trifluoromethyl, and (8) heteroaryl, wherein heteroaryl is selected fromtriazolyl, tetrazolyl, oxazolyl, pyrrolyl, imidazolyl, indolyl, pyridyl,and pyrimidinyl.
 8. The compound of claim 1 or a pharmaceuticallyacceptable salt thereof wherein R³ is methyl.
 9. The compound of claim 1or a pharmaceutically acceptable salt thereof wherein R⁵ is selectedfrom the group consisting of: hydrogen, methyl, cyclopropyl, chloro,—O—CH₃ and —S—CH₃.
 10. The compound of claim 1 or a pharmaceuticallyacceptable salt thereof wherein R⁶ is selected from the group consistingof: (1) hydrogen, (2) C₁₋₆ alkyl, (3) C₂₋₆ alkenyl, and (4) —(CO)—O—C₁₋₆alkyl.
 11. A compound which is selected from the group consisting of:2-(((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)amino)isonicotinonitrile;3-methoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]amino}pyridine-4-carbonitrile;2-(((3R,6R)-1-(2-(2H-tetrazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)amino)isonicotinonitrile;2-(((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)amino)-3-methylisonicotinonitrile;3-methyl-2-{[(3R,6R)-6-methyl-1-{[2-(2H-tetrazol-2-yl)phenyl]carbonyl}piperidin-3-yl]amino}pyridine-4-carbonitrile;2-((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)thiophene-3-carbonyl)-6-methylpiperidin-3-ylamino)-3-methoxyisonicotinonitrile;3-methoxy-2-((3R,6R)-6-methyl-1-(2-(pyrimidin-2-yl)thiophene-3-carbonyl)piperidin-3-ylamino)isonicotinonitrile;2-(((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)(methyl)amino)isonicotinonitrile;2-{methyl[(3R,6R)-6-methyl-1-{[2-(2H-tetrazol-2-yl)phenyl]carbonyl}piperidin-3-yl]amino}pyridine-4-carbonitrile;3-methoxy-2-{methyl[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl]carbonyl}piperidin-3-yl]amino}pyridine-4-carbonitrile;3-methoxy-2-(methyl{(3R,6R)-6-methyl-1-[(2-pyrimidin-2-ylthiophen-3-yl)carbonyl]piperidin-3-yl}amino)pyridine-4-carbonitrile;2-{ethyl[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]amino}pyridine-4-carbonitrile;2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl](prop-2-en-1-yl)amino}pyridine-4-carbonitrile;2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl](propyl)amino}pyridine-4-carbonitrile;N-((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-yl)-N-(4-cyanopyridin-2-yl)acetamide;methyl4-cyano-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]amino}pyridine-3-carboxylate;and methyl4-cyano-2-({(3R,6R)-6-methyl-1-[(2-pyrimidin-2-ylphenyl)carbonyl]piperidin-3-yl}amino)pyridine-3-carboxylate;or a pharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition which comprises an inert carrier and a compound of claim 1or a pharmaceutically acceptable salt thereof.
 13. (canceled) 14.(canceled)
 15. A method for enhancing the quality of sleep in amammalian patient in need thereof which comprises administering to thepatient a therapeutically effective amount of the compound of claim 1 ora pharmaceutically acceptable salt thereof.
 16. A method for treatinginsomnia in a mammalian patient in need thereof which comprisesadministering to the patient a therapeutically effective amount of thecompound of claim 1 or a pharmaceutically acceptable salt thereof.
 17. Amethod for treating or controlling obesity in a mammalian patient inneed thereof which comprises administering to the patient atherapeutically effective amount of the compound of claim 1 or apharmaceutically acceptable salt thereof.